The present invention relates to a pressure-liquefied propellant mixture based on hydrofluoroalkanes, to a medicinal aerosol formulation which contains such a propellant mixture, and to a process for the preparation of the aerosol formulation.
Many gases, such as, for example, carbon dioxide and nitrogen, can admittedly be liquefied under pressure, but are not suitable as propellants for metered aerosols because the internal pressure in the container decreases very considerably with increasing emptying. For these reasons, only those propellant gases which can be liquefied at room temperature and only lead to a slight decrease in the internal pressure when the contents are successively sprayed are suitable for medicinal metered aerosols. These include the propellant-type alkanes, such as, for example, propane, butane and isobutane, and also the chlorofluorocarbons (CFCs), such as, for example, trichlorofluoromethane (F11), dichlorodifluoromethane (F12) and 1,2-dichloro-1,1,2,2-tetrafluoroethane (F114).
For aerosol applications such as hairsprays, deodorant sprays and the like, occasionally combinations of propellants have also been proposed.
For example, WO-A-94/01511 discloses aerosol formulations formed from a compressed gas (nitrogen, carbon dioxide, compressed air, oxygen, xenon and/or argon), a liquefied hydrocarbon propellant, active compound and carrier, where the formulations can typically contain 0.05-2.5% by weight of nitrogen and 1.0-12.0% by weight of liquefied hydrocarbon propellant and preferably have a content of 80-95% by weight of volatile carrier compounds, such as ethanol, propanol, pentane, water, acetone and the like. In the Derwent Abstract AN 86-228980, a dermatophytic agent is furthermore described, which contains 0.1-2% by weight of tolunaphthate, 0.5-70% by weight of propellant and 30-80% by weight of fluorinated alkyl halide (trichloromonofluoromethane, tetrachlorodifluoroethane, trichlorotrifluoroethane and/or dibromotetrafluoroethane) having a boiling point of at least 20xc2x0 C. as a solvent; as a propellant, petroleum gas, dimethyl ether, dichlordifluoromethane, dichlorotetrafluoroethane, carbon dioxide etc. should be suitable. On the other hand, WO-A-93/17665 discloses a method for the administration of physiologically active compounds, in which a supercritical liquid solution is formed from a supercritical liquid solvent and the active compound and this is then moved into the subcritical range. As supercritical solvents, carbon dioxide, dinitrogen monoxide, chlorofluorocarbons, xenon, sulphur hexafluoride, ethanol, acetone, propane and/or water should be suitable.
On account of the ozone problem, caused by the removal of free-radical chlorine atoms from the CFCs, many countries came to an understanding in the Montreal Agreement no longer to use the CFCs as propellants in future. Suitable CFC substitutes for the medicinal area are fluorinated alkanes, especially 1,1,1,2-tetrafluoroethane (HFA 134a) and l,1,1,2,3,3,3-heptafluoropropane (HFA 227), since these are inert and have a very low toxicity. On account of their physical properties, such as pressure, density, etc., they are particularly suitable to replace the CFCs such as F11, F12 and F114 as propellants in metered aerosols.
U.S. Pat. No. 4,139,607 furthermore proposed a propellant system formed from liquefied bis(difluoromethyl) ether and gaseous carbon dioxide, which unlike combinations of carbon dioxide with other known propellants such as trichlorofluoromethane or methylene chloride should produce satisfactory aerosol patterns, but which has not been successful. According to the disclosure of U.S. Pat. No. 4,139,607, other, conventional propellants such as dinitrogen monoxide, hydrocarbons and fluorocarbons or liquid carriers, such as ethanol, perchloroethylene, trichloroethylene, acetone, amyl acetate, water and the like, can be added to the propellant system, ethanol and bis(difluoromethyl) ether in the weight ratio of approximately 1:1 usually being used in the examples disclosed. On the other hand, it is stated in the Derwent Abstract AN 89-184245 that hydrocarbons, such as butanes and pentanes, other compressed gases, such as carbon dioxide, dimethyl ether, nitrogen and dinitrogen oxide, or fluorocarbons could also be used instead of CFCs in aerosol pressure packs for the administration of medicaments.
CFC-free medicinal aerosol preparations containing HFA 134a are already encompassed by the general teaching of U.S. Pat. No. 2,868,691 and U.S. Pat. No. 3,014,844 and disclosed in DE-A-2 736 500 and EP-A-0 372 777. Examples containing HFA 227 are found in WO-A-91/11495, EP-A-0 504 112 and EP-B-0 550 031. It is known from various publications that the customary auxiliaries used in CFC-containing metered aerosols, such as, for example, lecithin, sorbitan trioleate and oleic acid, only dissolve inadequately in hydrofluoro-alkanes (in the context of the present invention designated by xe2x80x9cHFAxe2x80x9d), such as, for example HFA 134a and HFA 227, because chain lengthening and the substitution of the chlorine atoms by fluorine atoms leads to a worsening of the solubility properties for polar substances. Even in the case of the CFCs, which in comparison to the HFAs are considerably better solvents, ethanol or other cosolvents were often added to improve the solubility in order to be able to administer pharmaceuticals such as, for example, isoprenaline and epinephrine (cf. U.S. Pat. No. 2,868,691) as an aerosol. It was therefore obvious to improve not only the solubility of the CFCs, but also that of the HFAs, by addition of ethanol. Examples of this are found in the specialized literature and in various patent applications. Alternatively to this, there are a number of developments of aerosol preparations containing HFA 134a and/or HFA 227 liquefied under pressure, which use propellant-soluble auxiliaries, such as, for example, fluorinated surface-active substances (WO-A-91/04 011), mono- or diacetylated glycerides (EP-A-0 504 112) or polyethoxylated compounds (WO-A-92/00 061), which can dissolve in the two propellants in the necessary amount without addition of ethanol. Hitherto, however, only one product based on HFAs has been permitted as a bioequivalent substitute, namely a suspension aerosol formulation of salbutamol sulphate in HFA 134a, ethanol and oleic acid (Airomir(copyright), 3M Health Care Ltd., England).
For new developments of medicinal, CFC-free aerosol preparations, hydrofluoroalkanes such as HFA 134a (vapour pressure about 6 bar at 20xc2x0 C.) and HFA 227 (vapour pressure about 4.2 bar at 20xc2x0 C.) are preferably used today as propellants. Both propellants differ with respect to their density (about 1.4 mg/ml for HFA 227 and 1.2 mg/ml for HFA 134a at 20xc2x0 C.), which is important, in particular for suspensions. If the active compound has a higher density than the propellant, sedimentation occurs, if its density is lower, flotation occurs. It therefore suggests itself under certain circumstances to use propellant mixtures to solve the problem and/or to add cosolvents such as ethanol, diethyl ether or other low-boiling solvents or propellants such as n-butane to lower the density. An important disadvantage of the HFAs is their low dissolving power in comparison to the CFCs, in particular in comparison to F11. The solvent properties decrease with increasing chain length in the sequence F11 greater than HFA 134a greater than HFA 227. For this reason, without increasing the hydrophilicity by addition of polar solvents, such as, for example, ethanol, the suspending auxiliaries customarily used in CFCs, such as sorbitan trioleate, lecithin and oleic acid, can no longer be dissolved and thus used in the customary concentrations (about 1:2 to 1:20, based on the active compound).
It is generally known that in the case of suspension formulations only active compound particles which are smaller than 6 xcexcm are respirable. For the desired deposition thereof in the lungs, these must therefore be comminuted before processing by means of special procedures, such as, for example, micronization (grinding). In the case of most active compounds, the grinding process leads to an increase in surface area, which is usually accompanied by an increase in the electrostatic charge. This can lead to agglomeration or coagulation in the aerosol preparation and, in general, complicates homogeneous active compound dispersion. As a result of the interfacial and charge activities, there is frequently an adsorption of active compound at interfaces, which leads, for example, to ring formation in the container at the site where the liquid phase changes into the gas phase. In addition, the suspensions can often only be inadequately stabilized or kept in the dispersed state, which can also be linked with a change in the dose per puff if before use, i.e. before inhalation, the suspension cannot be homogeneously redispersed by shaking. The imperfect wetting or dispersion of the active compound particles also results in these in many cases having a high adsorption tendency and adhering to surfaces, such as, for example, the container inner wall or the valve, which then leads to a putative underdosage and to poor dosage accuracy in the spray burst or the content uniformity (CU) of the declared number of, for example, 200 or 300 spray bursts (i.e. individual doses). In the case of suspensions, as a rule it is therefore necessary to add a surface-active auxiliary or a lubricant, because otherwise jamming of the valves and an inaccurate delivery of the active compound from spray burst to spray burst can occur. Particularly problematical is a change or reduction of the inhalable, respirable particles, of the so-called xe2x80x9cfine particle fractionxe2x80x9d (FPF), occurring during storage, which leads to a decrease in the activity of the HFA preparation.
To overcome the problems presented above, it is possible, for example by pharmaceutical technology measures, to change the wetting and solubility properties of the active compound. As a rule, however, surface-active substances are added, such as were already used earlier in the CFC-containing formulations. Because, however, surface-active agents such as oleic acid and lecithin only dissolve inadequately in hydrofluoroalkanes such as HFA 134a and/or HFA 227, a cosolvent such as ethanol is usually added in order that the pharmaceutical technology problems can be better controlled.
If higher ethanol concentrations are added, the density of the propellant mixture is lowered which, especially in the case of suspensions, can lead to undesired active compound sedimentation. In addition, however, as a result of the increase in solubility, partial dissolution effects can occur during storage, which then lead to crystal growth. This effect as well as an agglomeration of the active compound particles can then lead in the course of storage to a change or lowering of the inhalable, respirable particles, the so-called xe2x80x9cfine particle fractionxe2x80x9d (FPF).
To measure the aerodynamic particle size distribution and the fraction, the mass or the dose of the inhalable, respirable particles (i.e. the fine particle fraction FPF, fine particle mass FPM or fine particle dose FPD), impacters such as, for example, the 5-stage multistage liquid impinger (MSLI) or the 8-stage Andersen cascade impacter (ACI), which are described in chapter 601 of the United States Pharmacopoeia (USP) or in the Inhalants Monograph of the European Pharmacopoeia (Ph. Eur.), are suitable.
With the aid of the aerodynamic particle size distribution, it is possible by means of a xe2x80x9clog-probability plotxe2x80x9d (logarithmic presentation of the probability distribution) to estimate the mass median aerodynamic diameter (MMAD) of aerosol preparations and deduce whether the active compound is deposited more easily in the upper or lower lung region.
If the active compound is present in the HFA propellant gas/ethanol mixture not in suspended form, but dissolved form, problems with respect to the scattering of the dosage accuracy per puff are usually less pronounced.
With the same ethanol content, a larger percentage of inhalable (smaller) particles are obtained with HFA 134a in comparison with HFA 227, which is to be attributed to the higher pressure of HFA 134a. In principle: the higher the internal pressure in the aerosol container, the finer the particle spectrum of the aerosol cloud. Solution aerosols containing a low proportion of ethanol as a rule have a smaller MMAD (0.8-1.5 xcexcm) when using fine atomizing nozzles than suspension aerosols (2-6 xcexcm). This is connected with the fact that droplets are produced in solution aerosols and particles in suspension aerosols.
For the topical application of active compounds in the area of the bronchi and bronchioles, particle sizes of about 2-4 xcexcm are advantageous, such as are customarily achieved with suspension formulations. Smaller particles which reach the alveolar area are partly exhaled ( less than 0.5 xcexcm) or reach the systemic circulation as a result of absorption. It follows from this that aerosol preparations for systemic application favourably should have particle sizes of about 0.5 xcexcm-2 xcexcm, where, for example, a monodisperse aerosol having a very high proportion of particles in the range of about 1 xcexcm would be particularly advantageous. Depending on the desired deposition site, a smaller or larger MMAD and optionally a monodisperse distribution spectrum is therefore preferred. With respect to the aerodynamics: the greater the mass of the particles the larger their tendency to continue flying in a straight line. It results from this that in the case of a change in the flow direction impaction of particles occurs. It is known from deposition studies that even with an optimal inhalation manoeuvre only about 20% of the particles emitted from a metered aerosol reach the lungs and almost 80% impact in the oropharynx.
In the case of ethanol-containing solution aerosols, unfortunately problems often occur relating to the active compound stability. The degree of decomposition of active compound, such as, for example, budesonide, fenoterol HBr, formoterol fumarate, ipratropium bromide, salbutamol, etc., can be above the tolerated highest values ( less than 0.5%) after storage in ethanol-containing solution aerosols. It is additionally disadvantageous that at higher ethanol concentrations of, for example, 10%-30% the proportion of inhalable particles ( less than 6 xcexcm) decreases, because as a result of the different evaporation characteristics of ethanol less energy is provided for the dispersion of the aerosol preparation, i.e. for the formation of inhalable droplets or particles. These and other reasons indicate why most metered aerosols have been brought onto the market as suspensions.
On account of the relationships presented above, it would thus be desirable for metered aerosols to have a propellant system with which:
active compounds can be better wetted;
suspension aerosols having improved suspension and shelf life properties can be prepared;
solution aerosols having improved storage stability and lower ethanol addition can be prepared;
the dosage accuracy can be improved;
the particle sizes or the particle size distribution spectrum can be better adjusted; and
the fine particle dose can be increased.
This object is achieved according to the invention by use of a propellant mixture based on carbon dioxide and at least one hydrofluoroalkane having 1 to 3 carbon atoms.
It has namely been found that carbon dioxide dissolves in the hydrofluoroalkanes and virtually loses its properties as a compressible gas. With increasing emptying, hydrofluoroalkane/carbon dioxide propellant mixtures of this type show only a slight decrease of the internal pressure in the container, which makes possible their use as propellants for metered aerosols. As a result of the addition of carbon dioxide to the hydrofluoroalkanes, the pressure increases approximately linearly with increasing carbon dioxide concentration. Furthermore, the pressure course as a function of the temperature is affected by the content of carbon dioxide to the effect that unlike pure hydrofluoroalkanes (cf. FIG. 2 of EP-B-0 550 031) only a weakly exponential, nearly linear pressure rise occurs if the temperature is increased stepwise, for example, from 20xc2x0 C. to 50xc2x0 C. These effects are also observed if the propellant mixture additionally contains a cosolvent.